Discovery of 2-(4-chloro-3-(trifluoromethyl)phenyl)-N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)acetamide (CHMFL-KIT-64) as a Novel Orally Available Potent Inhibitor against Broad Spectrum Mutants of c-KIT Kinase for Gastrointestinal Stromal Tumors

Starting from our previously developed c-KIT kinase inhibitor CHMFL-KIT-8140, through a type II kinase inhibitor binding elements hybrid design approach, we discovered a novel c-KIT kinase inhibitor compound 18 (CHMFL-KIT-64), which is potent against c-KIT wt and a broad spectrum of drug resistant mutants with improved bioavailability. 18 exhibits single digit nM potency against c-KIT kinase and c-KIT T670I mutant in the biochemical assay and displays great potencies against most of the gain-of-function mutations in the juxtamembrane domain, drug resistant mutations in the ATP binding pocket (except V654A) and activation loops (except D816V). In addition, 18 exhibits good in vivo PK profile in different species including mice, rats and dogs. It also displays good in vivo antitumor efficacy in the c-KIT T670I, D820G and Y823D mutants mediated mice models as well as in the c-KIT wt patient primary cells which are known to be imatinib-resistant. The potent activity against a broad spectrum of clinically important c-KIT mutants combining the good in vivo PK/PD properties of 18 indicate that it might be a new potential therapeutic candidate for gastrointestinal stromal tumors.